Melatonin, represented by the structure below ##STR1## is named systematically as N-[2-(5-methoxy-3-indolyl)ethyl]acetamide. Trivial names for the compound include N-acetyl-5-methoxytryptamine and N-acetyl-O-methylserotonin. Melatonin is a pineal gland hormone which has ovulation inhibitory activity, Chu, et al., Endocrinology, 75: 238 (1964), as well as some activity against MCF-7 human breast cancer cells, Blask et al. J. Neural. Transm. [Supp.], 21: 433-449 (1986) and for the treatment of mammalian breast carcinoma, Blask, et al., Neuroendocrinol. Lett., 9, No. 2: 63-73 (1987).
Several melatonin analogues of the formula ##STR2## wherein R.sup.1 is H, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkoxy;
R.sup.2 is H or C.sub.1 -C.sub.4 alkyl; PA1 R.sup.3 is H or methyl; PA1 R.sup.4 is H, haloacetyl, C.sub.1 -C.sub.5 alkanoyl, benzoyl, or benzoyl substituted with halo or methyl; PA1 R.sup.5 and R.sup.6 are individually H or halo; and PA1 R.sup.7 is H or C.sub.1 -C.sub.4 alkyl; PA1 R.sup.2 is H or C.sub.1 -C.sub.4 alkyl; PA1 R.sup.3 is H or methyl; PA1 R.sup.4 is H, haloacetyl, C.sub.1 -C.sub.5 alkanoyl, benzoyl, or benzoyl substituted with halo or methyl; PA1 R.sup.5 and R.sup.6 are individually H or halo; PA1 R.sup.7 is H or C.sub.1 -C.sub.4 alkyl;
provided that when R.sup.2 is H, at least one of R.sup.5 and R.sup.6 is halo; or when R.sup.5 and R.sup.6 are H, R.sup.2 is C.sub.1 -C.sub.4 alkyl, have also been prepared and have been shown to possess ovulation inhibition activity. See U.S. Pat. Nos. 4,997,845 and 4,614,807. However, none of these analogues were previously shown to possess activity against hormonally dependent mammalian breast carcinoma.
Tamoxifen (1-p-.beta.-dimethylaminoethoxyphenyl-trans-1,2-diphenylbut-1-ene), represented by the structure ##STR3## is a well-known antiestrogen compound having activity against mammalian breast carcinoma. See The Merck Index, 11th Ed., 1430 (1989). Furthermore, tamoxifen analogues also have antiestrogenic activity, including activity against mammalian breast carcinoma (U.S. Pat. No. 4,623,660). Numerous other compounds have similarly shown antiestrogenic activity resulting in suppression of mammalian breast tumor growth. For example, 2-phenyl-3-aroylbenzothiophenes and 2-phenyl-3-aroylbenzothiophene-1-oxides were disclosed in U.S. Pat. No. 4,133,814; 3-phenyl-4-aroyl-1,2-dihydronaphthalenes and 1-aroyl-2-phenylnaphthalenes were described in U.S. Pat. No. 4,230,862; and 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b ]thiophene was taught in U.S. Pat. No. 4,418,068.
Although tamoxifen has been studied in combination with cyclophosphamide as an intravenous injection, Abram et al., Br. J. Cancer, 57: 604-607 (1988), combinations of the above-mentioned melatonin analogues and antiestrogenic compounds, including tamoxifen, have not been tried for the treatment of hormonally dependent mammalian breast carcinoma.
It is the purpose of this invention to provide a method for the treatment of hormonally dependent mammalian breast carcinoma employing certain melatonin analogues. A further purpose of this invention provides a method for the treatment of hormonally dependent mammalian breast carcinoma employing a combination of certain melatonin analogues plus antiestrogen compounds which, when administered in adequate amounts, is synergistically effective against such carcinomas.